Camptothecin is an alkaloid, which demonstrated a wide spectrum of antitumor activity, in particular against colon tumors, other solid tumors and leukemias, and the first clinical trials were performed in the early 70's.
Since Camptothecin (CPT) has low water solubility and is rather toxic, a number of derivatives were proposed in the art in order to make available better drugs, in particular with lower toxicity and higher water solubility.
Many camptothecin derivatives were prepared and made available in the art through several synthetic routes.
The quality of the final product, such as its purity level or the easiness of isolation may depend also on the synthetic route and the kind of intermediate products.
In patent EP 1 044 977 and in Dallavalle S. et al., J. Med. Chem. 2001, 44, 3264-3274, camptothecin derivatives bearing an alkyloxime O-substituted at position 7 and endowed with antitumor activity higher than the compound of reference topotecan are described. Moreover these camptothecin derivatives bearing an imino group on position 7, also show an improved therapeutic index. One of the preferred molecules is 7-t-butoxyiminomethylcamptothecin (CPT 184) and known under the INN name Gimatecan.
7-(dimethoxy-methyl)camptothecin is disclosed in EP 0 056 692 and in Sawada, S., et al., Chemical & Pharmaceutical Bulletin (1991), 39(10), 2574-80.
This compound is used in different patents as intermediate in the synthesis of camptothecin derivatives.
7-(dimethoxy-methyl)-camptothecin can be prepared by ordinary acetalization of camptothecin 7-aldehyde, for example by heating camptothecin 7-aldehyde in hot methanol in the presence of an acid. Alternatively, this compound can be prepared in a single step by treating 7-hydroxymethylcamptothecin with an acid in the presence of methanol, see the above mentioned EP 0 056 692.
Acetalization is an equilibrium reaction and the starting aldehyde can be present in a certain amount. Moreover, acetals can be converted in the starting aldehyde in the presence of acids.
It is well-known that aldehydes are not endowed with high stability and they tend to polymerize giving side products which are difficult to eliminate from reaction mixtures and affect the purity of the final product.
The absence of the aldehyde allows crystallization and elimination of other unwished impurities, which can be present both in the starting material and derive from the reaction. For example, 9, 10 and 11 hydroxy- and methoxy-camptothecins (see below general formula 1), mappicine (see below general formula 2), and their derivatives are side derivatives produced in the reaction of formation of 7-(dimethoxy-methyl)camptothecin.

WO2006/067092 discloses a stereoselective process for the preparation of crystalline forms of Gimatecan. This process allows the stereoselective preparation of Gimatecan. With the addition of further dissolution and precipitation steps carried out in appropriate different solvent mixtures, four new crystalline forms of Gimatecan are also obtainable by using the same stereoselective process.
7-(dimethoxy-methyl)camptothecin is only mentioned as starting material, with no characterization.
WO03/101995 discloses camptothecins with a modified lactone ring and 7-(dimethoxy-methyl)camptothecin is used as intermediate in the synthesis of the final products. 7-(dimethoxy-methyl)camptothecin preparation is provided as purified from column chromatography and as a yellow solid with m.p. 201° C. (dec.). Product yield is 55%.
In the above mentioned Chemical & Pharmaceutical Bulletin (1991), 39(10), 2574-80 and in EP 0 056 692, the 7-(dimethoxy-methyl)camptothecin is disclosed as purified from column, m.p. 222-224° C. (dec.) and needle crystal.
Pharmaceutical legislations are stricter and stricter on safety issues concerning drug manufacturing. One aspect is Good Manufacturing Practice (GMP, see for Example EMEA and FDA Guidelines) and a sensitive topic is represented by standardization of intermediate compounds and impurity levels.
There is still the need of a form of 7-(dimethoxy-methyl)camptothecin of higher purity and that can be used for subsequent preparation of camptothecin derivatives to be used as drugs, meeting the severe regulatory requirements easier.
From a regulatory point of view, a high purity intermediate means a higher purity final product, with more severe specifications, therefore lesser quality variability. This latter aspect is requested and appreciated by Regulatory Authorities. Moreover, crystallization of an intermediate product represents an optimal purification step, allowing a better control of final quality, thus meeting GMP requirements easier and facilitating the whole production process. In this context, WO/03101995 does not teach any crystallization.
Another, additional need in synthesis of drugs is the stability of intermediate compounds. Stability is a desirable and necessary property for the intermediate compounds, since they are able to withstand chemical reaction conditions, in particular temperatures, without undergoing degradation or decomposition. More in particular, a high melting point, especially for those compounds which melt with decomposition, is recommended, as to avoid the presence in the reaction mixture of degradation side products, which make purification of the final product (the drug) much more difficult, even impossible.